Summary The long-term goal of this research project is to understand cellular, molecular, and epigenetic mechanisms of endocannabinoid (eCB) signaling that may modulate synaptic and neurocognitive functions. While the eCB system is known to play an important role in regulation of brain homeostasis, accumulated information suggests that the eCB system is also involved in several mental and neurological disorders. Augmentation of eCB signaling by inhibition of eCB metabolism has been proposed as a promising therapy for treatment and prevention of mental and neurocognitive illnesses. However, our understanding of the mechanisms underlying augmentation of eCB signaling by chronic inhibition of eCB metabolism in synaptic activity is still limited. Strengthening endocannabinoid 2-arachidonoylglycerol (2-AG) signaling by chronic inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes 2-AG in the brain, has been shown to produce antidepressant- and anxiolytic-like effects and enhance hippocampal synaptic plasticity as well as learning and memory. Our recent studies showed that sustained inactivation of MAGL increases the density of dendritic spines and expression of glutamate receptor subunits in the hippocampus. This suggests that augmentation of 2-AG signaling by inhibition of MAGL regulates structural and functional plasticity of synapses that determine activity of neural circuits and corresponding neurocognitive functions. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate expression and function of target molecules. However, we do not know whether miRNAs that target molecules involved in maintaining the integrity of synaptic structure and function are regulated by eCB signaling. In the proposed studies, we will test the hypothesis that regulation of synaptic activity and cognitive function by chronic inactivation of MAGL is through 2-AG signaling-mediated suppression of the miRNA that targets the molecules important for regulation of synaptic activity. The research proposed in this application is expected to further our understanding of the mechanisms underlying augmentation of eCB signaling in regulation of synaptic and neurocognitive functions, which may lead to future research on improving strategies for the treatment and prevention of mental and neurological illnesses.